Parathion organophosphate pesticides have been identified by the NINDS CounterACT Program as one of the highest priority chemical threats for civilians. Acute parathion exposure can cause death, severe seizures, brain injury, cognitive deficits and epilepsy and is a major risk for intentional use by terrorist groups for mass civilian exposure. Intentional contamination of food and water sources and high rise buildings represent a major threat for catastrophic terrorist attacks. This research proposal will have a significant impact on preventing mortality and morbidity from parathion exposure and will open a new horizon in our ability to understand the molecular mechanisms that mediate parathion toxicity. We propose to develop the first survival model in the rat for acute parathion toxicity and use this model to develop treatments to prevent mortality and morbidity. The BREAKTHROUGH for this project is the discovery using this parathion survival model of a molecular mechanism that potentially mediates many of the severe effects of parathion toxicity. We have discovered that parathion toxicity causes a long lasting increase in hippocampal neuronal calcium (Ca2+) induced Ca2+ release (CICR) from the endoplasmic reticulum in neurons and that this molecular alteration causes a Ca2+ plateau to develop in hippocampal neurons for more than a week after exposure. We propose to demonstrate that this altered Ca2+ signal underlies many of the morbidities of parathion exposure. This is a new discovery and potentially provides the first major insight into parathion toxicity. This research effort will test the CENTRAL HYPOTHESIS that it is possible to develop an animal model in the rat to evaluate parathion toxicity and to use this model to investigate mechanisms of toxicity that can then be targeted to develop CounterACT agents to reverse these mechanisms and prevent morbidity and mortality. We will test this hypothesis by conducting the following Specific Aims: Aim 1: Develop a model for parathion poisoning in the rat and determine the best CounterACT agents to prevent acute mortality. Aim 2: Determine the effect of parathion exposure on the development of the Ca2+ plateau. Aim 3: Determine whether administering inhibitors of CICR to intact animals after parathion exposure can prevent the development of the Ca2+ plateau in the intact animal model of parathion exposure. Aim 4: Determine whether administering inhibitors of CICR to intact animals after parathion exposure can prevent neuronal loss after exposure. Aim 5: Determine whether administering inhibitors of CICR to intact animals after parathion exposure can prevent cognitive impairment and the development of AE after parathion exposure. The preliminary results demonstrate the feasibility of these studies. These novel findings have opened a new frontier for research in understanding the causes of parathion toxicity. This work will have a high probability of having a sustained and powerful impact on our understanding of the cause of parathion toxicity and on our ability to target specific molecular mechanisms to prevent the severe mortality and morbidity associate with parathion exposure. PUBLIC HEALTH RELEVANCE: Parathion organophosphate pesticides have been identified by the NINDS CounterACT Program as one of the highest priority chemical threats for civilians. Acute parathion exposure can cause death, severe seizures, brain injury, cognitive deficits and epilepsy after civilian exposure. A major risk is the intentional use of parathion by terrorist groups for mass civilian exposure. Intentional contamination of food and water sources and high rise buildings represent a major threat for catastrophic terrorist attacks. The proposed studies offer a major breakthrough in our ability to develop agents to prevent death and the severe disabilities associated with parathion exposure. The results of this study have major clinical implications for treating parathion toxicity.